2-halo-5-phenyl-4h-3,5-dihydro-1,5-benzodiazepin-4-ones and salts thereof

ABSTRACT

Compounds of the formula   WHEREIN R1 and R2, which may be identical to or different from each other, are each hydrogen, straight or branched alkyl of 1 to 4 carbon atoms, di-lower alkylamino-(alkyl of 1 to 4 carbon atoms), hydroxy-(alkyl of 1 to 4 carbon atoms), alkenyl of 2 to 4 carbon atoms or, together with each other and the nitrogen atom to which they are attached, form a 6-membered saturated heterocyclic ring which may optionally have a methyl or tolyl substituent attached thereto, R3 is phenyl, o-halo-phenyl, o-nitro-phenyl or otrifluoromethyl-phenyl, and R4 is halogen, nitro or trifluoromethyl, AND NON-TOXIC, PHARMACOLOGICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF; THE COMPOUNDS AS WELL AS THEIR SALTS ARE USEFUL AS TRANQUILIZERS.

United States Patent Bauer et al.

[ Jan. 21, 1975 2-HALO-5-PHENYL-4H-3,5-DIHYDRO-l,5-

BENZODlAZEPlN-4-ONES AND SALTS THEREOF [75] Inventors: Adolf Bauer, lngelhelm/Rhein; Karl Heinz Weber; Klaus Minck, both of Gau-Algesheim; Peter Danneberg, Ingelheim/Rhein, all of Germany [73] Assignee: Boehringer Ingelheim G.m.b.l-l.,

lngelheim, Germany [22] Filed: Oct. 29, 1971 21 Appl. No.: 194,001

[30] Foreign Application Priority Data Nov. 2, 1970 Germany 2053680 [52] US. Cl 260/2393 B, 424/244, 424/250,

[51] Int. Cl C07d 53/04 [58] Field of Search 260/2393 B [56] References Cited UNITED STATES PATENTS 3,32l,468 5/1967 Krapcho et al 260/2393 B 3,644.374 2/1972 Buijle et al 260/293.88

OTHER PUBLICATIONS Buyle et a1, Tetrahedron, Vol. 25, pp. 3453-3459, (1969).

Primary Examiner-Henry R. Jiles Assistant ExaminerRobert T. Bond Attorney, Agent, or Firm-Hammond & Littell [57] ABSTRACT Compounds of the formula and non-toxic, pharmacologically acceptable acid addition salts thereof; the compounds as well as their salts are useful as tranquilizers.

1 Claim, No Drawings 2-HALO-S-PHENYL-4H-3,5-l)lHYDRO-l .5- BENZODlAZEmN-4-ONES AND SALTS THEREOF This invention relates to novel 2-amino-5-phenyl-4H- 3,5-dihydro-l,5-benzodiazepin-4-ones and non-toxic, pharmacologically acceptable acid addition salts thereof, as well as to a method of preparing these compounds.

More particularly, the present invention relates to a novel class of compounds represented by the formula R and R which may be identical to or different from each other, are each hydrogen, straight or branched alkyl of l to 4 carbon atoms, di-lower alkylamino(alkyl of 1 to 4 carbon atoms, hydroxy- (alkyl of l to 4 carbon atoms), alkenyl of 2 to 4 carbon atoms or, together with each other and the nitrogen atom to which they are attached, form a 6-membered saturated heterocyclic ring which may optionally have a methyl or tolyl substituent attached thereto,

R is phenyl, o-halophenyl, o-nitro-phenyl or o-trifluoromethyl-phenyl, and

R is halogen, nitro or trifluoromethyl, and non-toxic,

pharmacologically acceptable acid addition salts thereof.

The compounds embraced by formula I above may be prepared by reacting a compound of the formula X N C CH (II) u 2 m o wherein R and R have the same meaning as in formula I, and X is halogen, -OR or SR where R is alkyl of 1 to 4 carbon atoms, with an amine of the formula I (III) \RQI while cooling the solution, at room temperature or at a moderately elevated temperature.

If a compound of the formula I is to be prepared wherein R, and R have the same meanings as in formula 1 except the heterocyclic ring, such a compound may also be prepared by reacting the starting compound of the formula 11 in the above-described manner with ammonia and subsequently alkylating or dialkylating the resulting primary amino group in the 2-position by conventional methods with an alkylating agent, such as an alkyl halide, an alkyl sulfate or a dialkyl sulfate, or by means of the Leuckart-Wallach Reaction [see Berichte 18, 2341 (1885), and Annalen 272, (1892)].

The starting compounds of the formula 11 are also new; those wherein X is halogen may be prepared by reacting a compound of the formula t N c 4 0 CH2 IV) 1 c wherein R and R have the same meanings as in formula l, with an inorganic acid halide, preferably a phosphorus pentahalide, in the presence of an anhydrous inert organic solvent, such as dioxane, at a temperature between about 50 and +50C. Those compounds of the formula 11 wherein X is SR 0r-OR,-,, as defined above, may be obtained by selective conversion of the keto-group in the 2-position of the corresponding compound of the formula [V into the thiol group followed by alkylation, or by reacting a compound of the formula IV with the corresponding trialkyloxonium fluoroborate, as described in our copending application filed concurrently herewith and entitled 2-(Alkoxy or Alkylmercapto)-5-Phenyl-4H-3,5-Dihydro-l ,5- Benzodiazepin-4-ones."

However, a compound ofthe formula ll wherein X is -OR or SR as defined above, may also he prcpared by reacting a corresponding compound of the formula 11 wherein X is halogen with a corresponding alkanol or alkylmercaptan, respectively.

If the starting compound in the above process for the preparation of a compound of the formula I is a corresponding compound of the formula 11 wherein X is halogen, it is not necessary to isolate it from the reaction solution resulting from the reaction between the compound of the formula IV and the phosphorus pentahalide; the reaction with the amine of the formula 111 may be carried out in this reaction solution containing the imide halide.

The compounds of the formula I are organic bases and therefore form acid addition salts with inorganic or organic acids. Examples of non-toxic, pharmacologically acceptable acid addition salts are those formed with a hydrohalic acid, sulfuric acid, methanesulfonic acid, toluenesulfonic acid, 8-chlorotheophylline or the like.

Specific examples of end products of the formula I or non-toxic acid addition salts thereof which are obtained by the above-described procedures are the following:

2-amino-7-bromo-5-phenyl-4H-3,S-dihydro-l ,5-

benzodiazepin-4-one, 2-amino-7-chloro-5-phenyl-4H-3,S-dihydro-1,5-

benzodiazepin-4-one, 2-amino-5-phenyl-7-trifluoromethy1-4H-3,S-dihydro- 1,5-benzodiazepin-4-one, Z-amino-S -o-chlorophenyl-7-chloro4H-3,S-dihydro- 1,5-benzodiazepin-4-one, 2-amino-7-chloro-5-o-fluorophenyl-4H-3,5-dihydro- 1,5 -benzodiazepin-4-one, 2-amino-7-nitro-5-phenyl-4H-3 ,5-dihydro-1,5-

benzodiazepin-4-one, 2-amino-7-fluoro-5-phenyl-4H-3 ,5 -dihydro- 1 ,5-

benzodiazepin-4-one, Z-methylamino-S-phenyl-7-trifluoromethyl-4H-3 ,5-

dihydro-1,5-benzodiazepin-4-one, 7-chloro-2-methylamino-5 -phenyl-4H-3 ,S-dihydro- 1,5-benzodiazepin-4-one, 5-o-chlorophenyl-7-chloro-2-methylamino-4l-1-3 ,5-

dihydro-1,5-benzodiazepin-4-one, 2-methylamino-7-nitro-5 -phenyl-4H-3,5-dihydro- 1,5 -benzodiazepin-4-one, 7-chloro-2-methy1amino-5-o-nitropheny1-4H-3 ,5-

dihydro-l ,5-benzodiazepin-4-one, 5 7-bromo-2-methylamino-5-o-trifluoromethylphenyl- 41-1-3 ,S-dihydro- 1 ,5-benzodiazepin-4-one, 2-ethylamino-7-nitro-5-pheny1-4l-l-3,S-dihydro-1,5-

benzodiazepin-4-one, 2-ethylamino-7-chloro-5 -phenyl-41-1-3 ,S-dihydro- 1,5 -benzodiazepin-4-one,. 2-ethylamino-5-phenyl-7-trifluoromethyl-4H-3 ,5-

dihydro-l ,5-benzodiazepin-4-one, 2-tert.butylamino-7-chloro-5-phenyl-4H-3,5-

dihydrol ,5-benzodiazepin-4-one, 7-chloro-2-isopropylamino-5-phenyl-4l-1-3,5-

dihydro- 1 ,5-benzodiazepin-4-one, 2-isopropylamino-5-pheny1-7-trifluoromethyl-41-1- 3,5-dihydro-1,5-benzodiazepin-4-one,

2-isopropy1amino-7-nitro-5-phenyl-41-1-3,5-dihydro- 1,5-benzodiazepin-4-one, Z-n-butylamino-7-ch1oro-5-phenyl-41-1-3,S-dihydro- 1,5-benzodiazepin-4-one, Z-(B-hydroxyethyl-amino )-7-nitro-5-phenyl-4H-3,5-

5-phenyl-2-piperidino-7-trifluoromethyl-4H-3.5-

dihydro-l ,5-benzodiazepin-4-one, 7-nitro-5-phenyl-2-piperidino-4H-3,S-dihydrol ,5-

benzodiazepin-4-one, 7-chloro-2-(N'-methyl-pipera2ino)-5-phenyl-4H3.5

dihydro-l ,5-benzodiazepin-4-one. and 2-[N'-(o-methylphenyll-piperazino]-7-nitro-5- phenyl-4H-3,5-dihydrol ,5-benzodiazepin-4-one. The following examples further illustrate the present invention and will enable others skilled in the art to understand it more completely. It should be understood. however, that the invention is not limited solely to the particular examples given below.

EXAMPLE 1 2-Amino-7-chloro-5-phenyl-4H-3,5-dihydro-1,5- benzodiazepin-4-one and its hydrochloride A solution of 15 gm of -7-chloro-5-phenyl-4H-3,5- dihydro-l,5-benzodiazepin-2,4-dione in 500 ml of dry diethyleneglycol dimethylether was admixed at 15C. with 40 gm of phosphorus pentachloride and 0.4 ml of dimethylformamide, and the mixture was allowed to stand for 30 minutes. Thereafter, the reaction solution was poured into a solution of dry ammonia in methanol, the mixed solution was diluted with water and extracted three times with methylene chloride, and the combined extracts were evaporated in vacuo. The residue was dissolved in 60 ml of absolute acetone, the so lution was acidified with an excess of ethereal hydrochloric acid, ether was added to the acid solution, and the precipitate formed thereby, the hydrochloride of 2-amino-7-chloro-5-phenyl-4H3,5-dihydro-l,5- benzodiazepin-4-one, was collected by vacuum filtration. The filter cake was washed with ether and sus pended in water, the aqueous suspension was made alkaline with ammonia and then extracted with ethyl acetate, and the product was crystallized out by addition of ether, yielding 5.8 gm 39 percent of theory) of the compound of the formula NH N c 2 having a melting point of 242243C.

EXAMPLE 2 2-Amino-7-brom0-5-phenyl-4H-3,S-dihydro-1,5- benzodiazepin-4-one, its hydrochloride and its methanesulfonate 13 gm of 7-bromo-5-phenyl-lH-2,3,4,5-tetrahydro- 1,S-benzodiazepine-Z,4-dione were dissolved in one liter of hot dioxane, the solution was allowed to cool to 15C., and then, while stirring the solution, 50 gm of phosphorus pentabromide were added thereto. The mixture was allowed to react for 30 minutes, and then, while cooling and stirring, a vigorous stream of dry ammonia was passed therethrough until the resulting suspension reacted alkaline, taking care that the temperature did not rise above 20C. Subsequently, the suspension was evaporated in vacuo. the residue was admixed with aqueous ammonia, the resulting mixture was extracted several times with methylene chloride, and the combined extracts were washed with water vuntil neutral, dried with magnesium sulfate and evaporated in vacuo. The residue was taken up in acetone, the resulting solution was acidified with ethereal hydrochloric acid, and the precipitate formed thereby, i.e., the hydrochloride of 2-amino-7-bromo-5-phenyl-4H-3,5- dihydro-l,5-benzodiazepin-4-one, was collected by vacuum filtration. The filter cake was washed with ether and suspended in aqueous ammonia, the suspension was extracted with methylene chloride, the extract solution was dried with magnesium sulfate and evaporated, and the residue was recrystallized from isopropyl ether, yielding 8.2 gm (63 percent of theory) of the compound of the formula having a melting point of 248249C.

Its methanesulfonate had a melting point of 276-277.5C.

EXAMPLE 3 227228C. (recrystallized from ether), of the formula 2 N c Q CH2 in a manner analogous to Example 2.

Its methane sulfonate had a melting point of 247-249C.

EXAMPLE 4 2-Ethylamino-5-phenyl-7-nitro-4H-3,S-dihydro-1,5- benzodiazepin-4-one 2.0 gms of 2-methylmercapto-S-phenyl-7-nitro-4H- 3,5-dihydro-l,5-benzodiazepin-4-one were suspended in a mixture of 50 ml of ethanol and 5 ml of dimethylsulfoxide. While refluxing and stirring the suspension for minutes, a vigorous stream of gaseous ethylamine was passed therethrough, and then the resulting deep red solution was evaporated in vacuo. The residue was taken up in methylene chloride, the resulting solution was washed with water, dried over magnesium sulfate and evaporated, and the residue was recrystallized from ethanol, yielding 1.8 gm (91 percent of theory) of the compound of the formula having a melting point of 243245C.

EXAMPLE 5 Z-Methylamino-5-phenyl-7-trifluoromethyl-4H-3,5- dihydro-l ,5-benzodiazepin-4-one 1.2 gm of 2-ethoxy-5-phenyl-7-trifluoromethyl-4H- 3,5-dihydro-1,5-benzodiazepin-4-one were dissolved in a mixture of 30 ml of ethanol and 5 ml of dimethylsulfoxide, and, while stirring and refluxing the solution for six hours, a gentle stream of gaseous methylamine was passed therethrough. Thereafter, the reaction solution was allowed to cool to room temperature, was then saturated with gaseous methylami ne, and was allowed to stand at room temperature for 15 hours. Subsequently, the reaction solution was evaporated, the residue was taken up in methylene chloride, and the resulting solution was washed twice with water, dried over magne sium sulfate and evaporated. The residue was recyrstallized from a small amount of isopropyl ether, yielding 1.1 gm (95.5 percent of theory) of the compound of the formula having a melting point of 202203C.

EXAMPLE 6 2-Tert butylamino-7-chloro-5-phenyl-4H-3,S-dihydrol,5-benzodiazepin-4-one 15 gm of 7-chloro-5-phenyl-l H-2,3,4,5-tetrahydrol,5-benzodiazepine-2,4-dione in 750 ml of dioxane were stirred with 50 gm of phosphorus pentachloride, as described in Example 2, the reaction mixture was introduced into an excess of tert.butylamine on an ice bath, and the mixture was allowed to stand for 30 minutes. Thereafter, ice water was added, the aqueous mixture was admixed with 50 ml of ammonia, and the alkaline mixture was extracted with methylene chloride. The methylene chloride phase was washed with water, dried over magnesium sulfate and evaporated, and the residue was crystallized from methanol, yielding 14.3 gm (80.5 percent of theory) of the compound of the formula was prepared from 5-(o-fluoro-phenyl)-7-chloro-lH- N c/ 3 3 2,3,4,5-tetrahydro-l ,5-benzodiazepine-2,4-dione.

EXAMPLE l Using a procedure analogous to that described in Ex- Cl ample l, Z-amino-S-phenyl-7-nitro-4H-3.S-dihydn 6 5 fl,5-be]nzodiazepin-4-one. m. p. 2l9-Z20C.. of the 7.. e. ormua having a melting point of 275 276 C. /N c NH EXAMPLE 7 Z-Dimethylamino-S-phenyl-7-nitro-4H-3,S-dihydro- 2 l ,5-benzodiazepin-4-one O N 6% 2 gm of Z-amino-5-phenyl-7-nitro-4H-3,S-dihydrol5 l,5-benzodiazepin-4-one, 5 ml of methyl iodide and 1 gm of sodium methylate were dissolved in 30 ml of dimethylacctamide, and the ensuing exothermic reaction was interrupted after 30 minutes. Thereafter, the reaction solution was evaporated, the residue was taken up in ethyl acetate, and the resulting solution was ex- EXAMPLE H tracted with water. The organic phase was dried with magnesium sulfate and then evaporated, and the residue was recrystallized from ether, yielding 87 percent was prepared from 5-phenyl-7-nitro-lH-2,3,4,5- tetrahydro-l ,5-benzodiazepine-2,4-dione.

Using a procedure analogous to that described in Example l, 2-amino-5-phenyl-7-fluoro-4H-3,S-dihydro- 1,5-benzodiazepin-4-one, m. p. 222224C., of the of theory of the compound of the formula f l ormu a NH N c 3 2 N z 0 2 0 N 2 ll *0 l- C\\ havmg a meltmg pomt of 219 220 was prepared from 5-phenyl-7-fluorolH-2,3,4,5-

EXAMPLE 8 tetrahydro-l ,S-benzodiazepine-Z,4-dione. Usling a prgcedure gnilogiplus to tllliat dlesgribltled ll'lft- EXAMPLE 12 amp e -am1noo-c oro-p eny -c oro- Using a procedure analogous to that described in Ex- -4- dlhydro benzodlazepm one m p 40 ample 5, Z-methylammo-S-phenyl7-chloro-4H-3,5-

fth f l 260 262C 0 e ormua dihydro-l,5-benzodiazepm-4-one, m. p. 2l82l9C.,

/NH2 of the formula N: C C1 Nc C1- Cl O C6H5 was prepared from 5-(o-chloro-phenyl)-7-chloro-lH- 2,3,4,5-tetrahydro-l ,S-benzodiazepine-Z,4-dione.

NH-CH3 was prepared from 2-ethoXy-5-phenyl-7-chloro-4H- 3,5-dihydro-l,5-benzodiazepin-4-one and methyl- EXAMPLE 9 amine. Using a procedure analogous to that described in Ex- EXAMPLE 3 g fi fl i ggg ggggg s iiggz fQ Using a procedure analogous to that described in Exthe ample 4, 2-ethylamino-S-phenyl-7-chloro-4H-3,5-

dihydro-l,5-benzodiazepin-4-one, m. p. 183-l84C.,

NH of the formula N C/ 2 NH 0 H \CH2 N 7/ 2 5 c CH I s C1 3,862,136 9 10 was prepared from Z-methylmercapto-S-phenyl-7- 4H-3,5-dihydro-l,5-benzodia2epin-4-one. m. p. 277C. chloro-4H'3,S-dihydro-l ,5-benzodiazepin-4-one and (decomp), of the formula ethylamine.

EXAMPLE 14 N wa Using a procedure analogous to that described in Example 6, Z-isopropylamino-5-phenyl-7-chloro-4H-3.5- dihydro-l,5-benzodiazepin-4-one, m. p. 240-24lC., F 0 of the formula I 5 NHCH(CH was prepared from 2-amino-5phenyl-7- 2 trifluoromethyl-4H-3,S-dihydro-l ,5-benzodiazepin- C1 N C/ 4-one and dimethylacetamide.

I o EXAMPLE 18 5 5 Using a procedure analogous to that described in Example 6, 2-(B-hydroxyethyl-amino)-5-phenyl-7- t'fl th l-4H-3,5-d'h -1, d' was prepared from 5-phenyl-7-chloro-lH-2,3,4,5- 1:33: 0 06 gaz lazepm tetrahydro-l,5-benzodiazepine-2,4-di0ne and isopropylamine. /NH CH2 CH2OH EXAMPLE 15 Using a procedure analogous to that described in Ex- I CH2 ample 7, 2-dimethylamino-5-phenyl-7-chloro-4H-3,5- F C N C dihydro-l,5-benzodiazepin-4-one, m. p. l42-l45C., 3 I of the formula C H 3O /N(CH3)2 N C was prepared from 5-phenyl-7-trifluoromethyl-1H- H 2,3,4,5-tetrahydro'I,S-benzodiazepine-Z,4-dione and 2 ethanolamine. C1 l C EXAMPLE 19 5 Using a procedure analogous to that described in Example 6, 2-isopropylamino-5-phenyl-7-trifluoromethyl- 4H3,5-dihydro-l ,5-benzodiazepin-4-one, m. p.

was prepared from 2-amino-5-phenyl-7-chloro-4H-3,5- 215 217 C fth f l o e ormu a dihydro-l,5-benzodiazepin-4-one and dimethylacetamide.

EXAMPLE 16 N C, NH-CH(CH Using a procedure analogous to that described in Ex- 45 ample 5, Z-methylamino-5-(o-chloro-phenyl)-7- 2 chloro-4H-3,5-dihydro-l,5-benzodiazepin-4-one, m. p. F C 224225C., of the formula 3 1 C6H5 NHCH was prepared from 5phenyl-7'trifluoromethyl-lH- H 2,3,4,5-tetrahydro-l,5-benzodiazepine-2,4-dione and 2 isopropylamine. c1 c l 0 EXAMPLE 20 Cl Using a procedure analogous to that described in Example 4, 2-ethylamino-5-phenyl-7-trifluoromethyl-4H- 3 ,S-dihydro-l ,5-benzodiazepin-4-one, m. p.

18ll83C., of the formula was prepared from 2-ethoxy-5-(o-chloro-phenyl)-7- chloro-4H-3 ,5-dihydro- 1 ,5 -benzodiazepin-4-one and NH C2H5 methylamine. N C

ca EXAMPLE 17 w 2 Using a procedure analogous to that descr1bed in Example 7, 2-dimethylamino-5-phenyl-7-trifluoromethyl- 5 was prepared from 2-methylmercapto-5-phenyl-7- trifluoromethyl-4H-3,5-dihydro-l ,S-benzodiazepin- 4-one and ethylamine. 1

EXAMPLE 21 Using a procedure analogous to that described in Example 6, 2-[(B-dimethylamino-ethyl)-amino]-5- phenyl-7-trifluoromethyl-4H-3 ,S-dihydro-l ,5- benzodiazepin-4-one, m. p. l7l-l73C., of the formula was prepared from -phenyl-7-trifluoromethyl-ll-l- 2,3,4,5-tetrahydro-l,5-benzodiazepine-2,4-dione and N,N-dimethylethylenediamine.

EXAMPLE 22 Using a procedure analogous to that described in Example 6, 2-piperidino-5-phenyl-7-trifluoromethyl-4H- 3 ,S-dihydrol ,5-benzodiazepin-4-one, m. p. 144-l46C., of the formula was prepared from 5-phenyl-7-trifluoromethyl-lH- 2,3,4,5-tetrahydrol ,5-benzodiazepine-2,4-dione and piperidine.

EXAMPLE 23 Using a procedure analogous to that described in Example 6, 2-isopropylamino-5-phenyl-7-nitro-4H-3,5- dihydro-l,5-benzodiazepin-4-one, m. p. 25l253C., of the formula EXAMPLE 24 Using a procedure analogous to that described in Example 6, 2-piperidino-5-phenyl-7-nitro-4H-3,5-

dihydro-l ,5benzodiazepin-4-one, m. p. l176C., of the formula N N==C CH N 2 was prepared from 5-phenyl-7-nitro-lH-2,3,4,5- tetrahydro-l,5-benzodiazepine-2,4-dione and piperidine.

EXAMPLE 25 Using a procedure analogous to that described in Example 6, 2-[(B-dimethylamino-ethyl)-amino]-5- phenyl-7-nitro-4H-3,S-dihydrol ,S-benzodiazepin- 4-one, m. p. l48l53C., of the formula ca 2 2 2 Ce was prepared from 5-phenyl-7-nitrol H-2,3 ,4,5-

tetrahydro-l,5-benzodiazepine2,4-dione and N,l\l-

dimethyl-ethylenediamine.

EXAMPLE 26 Using a procedure analogous to that described in Example 6, 2-(N'-o-tolyl-piperazino)-5-phenyl-7-nitro- 4H-3 ,S-dihydro-l ,5-benzodiazepin-4-one, m. p. 223225C., of the formula g N z c\ CH CH 3 O N 1:1 0 0 was prepared from 5-phenyl-7-nitr0-lH-2,3,4,5- tetrahydro-l ,5-benzodiazepine-2,4-dione and N-o-tolyl-piperazine.

EXAMPLE 27 Using a procedure analogous to that described in Example 5, 2-methylamino-5-phenyl-7-nitro-4H-3,5- dihydro-l,5-benzodiazepin-4-one, m. p. 2l72l9C., of the formula N C NH-CH3 /CH was prepared from 2-ethoxy-5-phenyl-7-nitro-4l-l-3,5- dihydro-l ,5-benzodiazepin-4-one and methylamine.

EXAMPLE 2:; 5

Using a procedure analogous to that described in Example 6, Z-(B-hydroxyethyl-amino)-5-phenyl-7-nitro- 4H-3,5-dihydro-l ,5-benzodiazepin-4-one, m. p. l91193C., of the formula l0 NH-CHg-CH OH CH O C 2 was prepared from 5-phenyl-7-nitro-ll7l-2,3,4,5- tetrahydro-l ,5-benzodiazepin-2,4.-one and ethanolamine.

EXAMPLE 29 Using a procedure analogous to that described in Example 6, 2-(N'-methyl-piperazino)-5-phenyl-7-chloro- 4H-3,5-dihydro-1,5-benzodiazepin-4-one, m. p. 2l7-219C. (decomp.), of the formula 30 N h-CH3 was prepared from 5-phenyl-7-chlorolH-2,3,4,5- 4o tetrahydro-l ,5-benzodiazepine-2,4-dione and N-methyl-piperazine.

EXAMPLE 30 Using a procedure analogous to that described in Example 6, 2-[(B-dimethylamino-ethyl)-amino]-5- phenyl-7-chloro-4H-3 ,S-dihydrol ,S-benzodiazepin- 4-0ne, m. p. 278-280C., of the formula NH-CH -CH -N(CH N=C Cl 1;} C O was tetrahydro-l ,S-benzodiazepine 2,4-dione dimethyl-ethylenediamine.

prepared from 5-phenyl-7-chloro-lH2,3,4,5-

and N,N-

EXAMPLE 3] dihydro-l,5'benzodiazepin-4-one, m. p. l47l48C..

of the formula na-n-crpr EXAMPLE 32 Using a procedure analogous to that described in Example 6, 2-n-but-ylamin0-5-(o-trifluoromethyl-phenyl)- 7-chloro-4H-3,S-dihydro-l,5-benzodiazepin-4-one, m. p. l84l85C., of the formula was prepared from 5-(o-trifluoromethyl-phenyl)-7- chloro-l H-2,3,4,5-tetrahydro-l ,S-benzodiazepine-ZA- dione and n-butylamine.

EXAMPLE 33 Using a procedure analogous to that described in Example 6, 2-n-butylamino-5-(o-fluor0-phenyl)-7-chloro- 4H-3,5-dihydro-l ,5-benzodiazepin-4one, m. p. 200-202C., of the formula N NH-n-C4H was prepared from S-(o-fluoro-phenyl)-7-chloro-lH- 2,3,4,5-tetrahydrol ,5-benzodiazepin e-ZA-dione and n-butylamine.

EXAMPLE 34 Using a procedure analogous to that described in Example S. 2-mcthylamino-5-(o-nitro-phcnyl)-7-chloro- 4H-3.5-dihydro-l ,5-henzodiazepin-4-onc, m. p. 260262C., of the formula was prepared from 2-ethoxy-5-(o-nitro-phenyl)-7- chloro-4H-3,5-dihydro-l,5-benzodiazepin-4-one and methylamine.

EXAMPLE 35 Using a procedure analogous to that described in Example 6, 2-allylamino-5-phenyl-7-chloro-4l-l-3,5- dihydro-l ,5-benzodiazepin-4-one, m. p. l73l76C., of the formula /NH-CH2-CH=CH2 Q We c1 N c was prepared from 5-phenyl-7-chloro-lH-2,3,4,5- tetrahydro-l,5-benzodiazepine-2,4-dione and allylamine.

EXAMPLE 36 Using a procedure analogous to that described in Example 6, 2-diallylamino-S-phenyl-7-chloro-4l-l-3,5- dihydro-l,5-benzodiazepin-4-one of the formula CH -CH=CH 2 2 40 was prepared from 5-phenyl-7-chloro-lH-2,3,4,5- tetrahydro-l,5-benzodiazepine-2,4-dione and diallylamine. lts hydrochloride had a melting point of 200C. (decomp.).

EXAMPLE 37 Using a procedure analogous to that described in Example 6, 2-(N-n-butyl-ethylamino)-5-phenyl-7-chloro- 4H-3,5-dihydro-l ,5-benzodiazepin-4-one, m. p. l85l88C., of the formula Qt CH2 c1 prepared from 5-phenyl-7-chloro-lH-2,3,4,5-

and N-nwas tetrahydro-l ,S-benzodiazepine-Z,4- dione butyl-ethylamine.

EXAMPLE 38 Using a procedure analogous to that described in Exwas prepared from 5-phenyl-7-nitro-lH-2,3,4,5- tetrahydrol,5-benzodiazepin-2,4-dione and ammonia. lts methanesulfonate had a melting point of 238-239.5C.

The compounds according to the present invention, that is, those embraced by formula I and their nontoxic, pharmacologically acceptable acid addition salts, have useful pharmacodynamic properties. More particularly, the compounds of the instant invention exhibit tranquilizing activities in warm-blooded animals, such as dogs, rats, minks. Particularly effective tranquilizers are those compounds of the formula I wherein R is hydrogen or methyl, R is hydrogen, methyl or ethyl, R is phenyl, and R is halogen, nitro or trifluoromethyl, and their non-toxic acid addition salts.

In addition, the compounds of the present invention are useful as intermediates for the preparation of other tranquilizers of the benzodiazepine class.

For pharmaceutical purposes the compounds according to the present invention are administered to warmblooded animals perorally or parenterally as active ingredients in customary pharmaceutical dosage unit compositions, that is, compositions in dosage unit form consisting essentially of an inert pharmaceutical carrier and one effective dosage unit of the active ingredient, such as tablets, coated pills, capsules, wafers powders, solutions, suspensions, emulsions, syrups, suppositories and the like. One effective tranquilizing dosage unit of the compounds according to the present invention is from 0.0083 to 0.84 mgm/kg body weight, preferably from 0.0166 to 0.42 mgm/kg, and the preferred daily dose is from 0.083 to 2.5 mgm/kg body weight.

The following examples illustrate a few pharmaceutical dosage unit compositions comprising a compound of the present invention as an active ingredient and represent the best modes contemplated of putting the invention into practical use. The parts are parts by weight unless otherwise specified.

EXAMPLE 39 benzodiazepin-4-one HCl 5.0 parts Lactose 28.5 do. Corn starch l5.0 do. Gelatin 1.0 do.

Magnesium stearate 500 parts Total Preparation:

The benzodiazepinone compound is intimately admixed with the lactose and the corn starch, the mixture is moistened with an aqueous percent solution of the gelatin, the moist mass is forced through a l mm-mesh screen, the resulting granulate is dried at 40C. and again passed through the screen, the dry granulate is admixed with the magnesium stearate, and the composition is compressed into 50 mgr'n-pill cores which are subsequently coated in conventional manner with a thin shell consisting essentially of a mixture of sugar, titanium oxide, talcum and gum arabic, and finally polished with beeswax. Each coated pill contains 5 mgm of the benzodiazepinone compound and is an oral dosage unit composition with effective tranquilizing action.

The same result is obtained when an equal amount of one of the following 4H-3,5-dihydro-l,5- benzodiazepin-4-ones is substituted for the benzodiazepinone compound in the above pill core composition:

2-Amino-7-bromo-5-phenyl-4l-l-3 ,S-dihydro-l ,5-

benzodiazepin-4-one; 2-Amino-7-nitro-5-phenyl-4H-3,S-dihydro-l,5-

benzodiazepin-4-one;

2-Methylamino-5-phenyl-7-trifluoromethyl-4H-3 ,5-

dihydro-l ,5-benzodiazepin-4-one; 2-Dimethylamino-5-phenyl-7-trifluoromethyl4H- 3,5-dihydro-l ,5-benzodiazepin-4-one; or 2-Ethylamino-5-phenyl-7-trifluoromethyl-4H-3,5-

dihydro- 1 ,5-benzodiazepin-4-one.

EXAMPLE 40 Z-Amino-S-phenylJ-bromo-4H-3.5

dihydro-l ,5benzodiazepin-4-one 5.0 parts Suppository base (e.g. cocoa butter) l695.0 do.

Total l700.0 parts Preparation:

The finely pulverized benzodiazepinone compound is blended with the aid of an immersion homogenizer into the suppository base which had previously been melted.

and cooled to 40C. 1700 mgm-portions of the resulting composition are poured at 35C. into cooled suppository molds and allowed to harden. Each supposi' tory contains 5 mgm of the benzodiazepinone compound and is a rectal dosage unit composition with el fective tranquilizing action.

The same result is obtained when an equal amount of 2-amino-7-nitro-5-phenyl-4H-3,5-dihydro-l ,5- benzodiazepin-4-one is substituted for the henzodiazepinone compound in the above suppository composition.

Analogous results are obtained when any one of the other compounds embraced byvformula l or a non-toxic acid addition salt thereof is substituted for the particular benzodiazepinone in Examples 39 and 40. Likewise, the amount of active ingredient in these illustrative examples may be varied to achieve the dosage unit range set forth above, and the amounts and nature of the inert pharmaceutical carrier ingredients may be varied to meet particular requirements.-

While the present invention has been illustrated with the aid of certain specific embodiments thereof, it will be readily apparent to others skilled in the art that the invention is not limited to these particular embodiments, and that various changes and modifications may be made without departing from the spirit of the invention or the scope of the appended claims.

We claim:

1. A compound of the formula wherein R is phenyl, o-halo-phenyl, o-nitro-phenyl or o-trifluoromethyl-phenyl, R is halogen, nitro or trifluoromethyl, and X is chlorine or bromine. 

